Reduced bone quality is a key determinant of skeletal fragility in CKD, but the details of this effect are not well defined. Non-enzymatic collagen crosslinks (formed via advanced glycation end-products, AGEs) negatively affect bone mechanical properties and AGEs are elevated in the blood and bone of patients and animals with advanced CKD. We propose that skeletal accumulation of AGE collagen cross links may play a critical role in CKD skeletal fragility and reducing AGEs may represent a novel approach to reduce fracture risk in CKD patients. The overall goal of this study is to test the hypothesis that skeletal AGEs induce negative mechanical and cellular effects in CKD and that circulating AGE levels can help in CKD patient fracture discrimination. This goal will be accomplished through a combination of pre-clinical experiments using our established model of progressive CKD (the Cy/+ rat), novel human biopsy assays, and state-of-the art bone imaging with second generation high resolution peripheral quantitative computed tomography. The multi-university interdisciplinary team is perfectly positioned to undertake this translational work based on their clinical and preclinical expertise in bone, collagen/AGEs, mechanics, and CKD. In Aim 1 we will determine if AGE- lowering drug treatments that reduce endogenous AGE production or gastrointestinal absorption improve the skeletal properties of animals with progressive CKD. In Aim 2 we will assess the effect of disease severity on human bone AGE accumulation and its relationship to mechanical properties by measuring bone AGE levels and mechanical properties from transiliac crest bone biopsies from patients with CKD. In Aim 3, we will quantify the ability of AGE levels to improve fracture discrimination in CKD patients. In Aim 4, we will determine if AGE accumulation in the bone extracellular matrix impairs bone marrow derived osteoblast differentiation, function and AGE receptor expression. The current proposal will build on our body of work characterizing abnormal bone quality in patients with CKD by studying how agents that modulate AGEs through different mechanisms alter skeletal accumulation of AGEs and bone mechanical properties in animals and humans. If these studies show efficacy in benefiting skeletal mechanical properties, these treatments could be rapidly translated into the clinical setting.